The 1:2 complex between RavZ and LC3 reveals a mechanism for deconjugation of LC3 on the phagophore membrane
Open accessAbstract
Hosts utilize macroautophagy/autophagy to clear invading bacteria; however, bacteria have also developed a specific mechanism to survive by manipulating the host cell autophagy mechanism. One pathogen, Legionella pneumophila, can hinder host cell autophagy by using the specific effector protein RavZ that cleaves phosphatidylethanolamine-conjugated LC3 on the phagophore membrane. However, the detailed molecular mechanisms associated with the function of RavZ have hitherto remained unclear. Here, we report on the biochemical characteristics of the RavZ-LC3 interaction, the solution structure of the 1:2 complex between RavZ and LC3, and crystal structures of RavZ showing different conformations of the active site loop without LC3. Based on our biochemical, structural, and cell-based analyses of RavZ and LC3, both distant flexible N- and C-terminal regions containing LC3-interacting region (LIR) motifs are important for substrate recognition. These results suggest a novel mechanism of RavZ action on the phagophore membrane and lay the groundwork for understanding how bacterial pathogens can survive autophagy.
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Lipidation of LC3-family proteins is required for recycling of TLR4, TREM2, and CD36.
“The requirement for ATG4, which converts LC3 to LC3-I (Kabeya et al., 2004) and the effect of RavZ, which irreversibly cleaves lipidated LC3 (Choy et al., 2012; Kwon et al., 2017), strongly suggest that lipidation of LC3-family proteins is required for recycling of these receptors.”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Kwon et al., 2017
RavZ prevented receptor recycling.
“The Legionella-derived protease, RavZ, which irreversibly cleaves lipidated LC3 (Choy et al., 2012; Kwon et al., 2017) also prevented this receptor recycling, again, as defined by this method (Lucin et al., 2013; Yin et al., 2016).”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Kwon et al., 2017
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“, 2004) and the effect of RavZ, which irreversibly cleaves lipidated LC3 (Choy et al., 2012; Kwon et al., 2017), strongly suggest that lipidation of LC3-family proteins is required for recycling of these receptors.”
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- Authors
- Kwon, D. H., Kim, S., Jung, Y. O., Roh, K.-H., Kim, L., Kim, B.-W., Hong, S. B., Lee, I. Y., Song, J. H., Lee, W. C., Choi, E.-J., Hwang, K. Y., & Song, H. K.
- Affiliations
- Korea University (KR)
- Corresponding author
- Hwang, Kwang Yeon
- Song, Hyun Kyu
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2016-11-21
- Volume
- 13
- Issue
- 1
- Pages
- 70-81
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC5240826
- OpenAlex
- W2539732036
- Cited by
- 43
- References
- 49
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 7
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Figshare (cc-by)
- Funders
- National Research Foundation
- National Research Foundation of Korea (2015K2A2A6002008, 2011-0028168)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Legionella and Acanthamoeba research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- LC3, Legionella pneumophila, autophagy evasion, LC3-interacting region, protein-protein complex structure, substrate recognition, bacterial effector proteins, host-pathogen interaction
- MeSH terms
- Autophagy-Related Proteins, Protein Domains, Autophagy, Bacterial Proteins, Cysteine Endopeptidases, Humans, Legionella, Microtubule-Associated Proteins, Models, Molecular, Phagocytes, Phagosomes, Protein Binding, Scattering, Radiation, Crystallography, X-Ray, Catalytic Domain, Surface Plasmon Resonance, HEK293 Cells
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